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The Finnish Diabetic Nephropathy Study was founded to uncover the risk factors and mechanisms of the diabetic complications. We specialize in type 1 diabetes, where the body depletes its own capacity to use glucose via a deranged immune reaction, typically at a young age. We wish to improve the care for these patients by increasing the knowledge of the genes and environmental factors involved, and thus reduce the human and societal cost until a cure for diabetes itself - if ever found - is available. The study sample consists of type 1 diabetes cases and sibpairs that have been followed-up to monitor disease progress and complications (N=5500).

The Finnish Diabetic Nephropathy Study (FinnDiane) represents the largest and by far the most thoroughly characterized patient cohort of patients with type 1 diabetes with or without diabetic nephropathy in the world. The main aim is to explain why one third of patients with diabetes will develop diabetic nephropathy, a complication that is associated with a remarkably increased risk of premature mortality. In patients on dialysis or having received a kidney transplant the standardized mortality rate (SMR) is increased approximately 18-fold, in patients with macroalbuminuria 9-fold, and in patients with microalbuminuria 3-fold. However, if the patients have no signs of diabetic kidney disease, i.e. their albumin excretion rate is normal; there is no additional risk of premature mortality. Thus the increased risk of premature mortality is entirely due to diabetic nephropathy (Groop et al. Diabetes 2009).In order to achieve the aim the FinnDiane Study Group has four legs (phenotyping team, genetics team, bioinformatics team and a cell and molecular biology team) that work in concert to dissect the pathogenesis of the devastating complication.

The phenotyping teamfocuses on the thorough clinical characterization of the patients including such methodologies as pulse wave analysis (tonometry), Holter-monitoring, 24-h blood pressure monitoring, ECG, cardioechography, spiroergometry, autonomic function testing, carotic IMT imaging, fundus photograpy, DEXA (bone density and body fat distribution), as well as a full clinical examination including questionnaires regarding the presence of complications, history of life style factors, physical exercise, diet, and psychological aspects. The team has published a number of papers showing that HbA1c variability (Wadén et al. Diabetes 2009), the metabolic syndrome (Thorn et al. Diabetes Care 2005), lipid abnormalities (Tolonen et al. Diabetologia 2008), high LPS at baseline (Nymark et al. Diabetes Care 2009), and chronic inflammation (Saraheimo et al. Diabetologia 2003) predict the development and progression of diabetic nephropathy. The team has also shown that type 1 diabetes is associated with a reduced baroreflex sensitivity (BRS), a predictor of cardiovascular disease in the general population, and that the reduced BRS can be restored by an easy maneuver like slow breathing (Rosengård-Bärlund et al. 2009). This is important since a reduced BRS has previously been interpreted as organic autonomic neuropathy, but our studies show that at least at the early stage the abnormality is still functional and reversible.

The genotyping teamis currently focusing on the analysis of the GWAS data from the FinnDiane cohort. At this stage there are a number of interesting hits (chromosomes 2, 3 and 4) that are now in the replication phase. In order to maximize the success rate the FinnDiane has liaised with groups from Boston, Dublin and Belfast (GENIE consortium). In collaboration with Professor Karl Tryggvason from the Karolinska Institute FinnDiane showed that a variant on chromosome 3 is strongly associated with diabetic nephropathy (He et al. Am J Hum Genet 2009). This variant is located in the close vicinity of the Nck1-gene, a gene that codes for the formation of podocytes. Knock-out mice have been generated in collaboration with Professor Susan Quaggin in Toronto. It was furthermore shown that proliferative diabetic retinopathy has a heritability rate of more than 50% (Hietala et al. Diabetes 2008). A key observation is that parental hypertension and type 1 and/or 2 diabetes are associated with increased risk of diabetic nephropathy in the offspring (Thorn et al. Diabetes Care 2009).

The bioinformatics teamhas brought on board a number of useful tools to analyze the huge amount of data FinnDiane is generating, tools such as self-organizing maps (SOM) (Mäkinen et al. 2008), estimation of VLDL, IDL, LDL, HDL2, apoA-1 and apoB from Friedewald inputs (Niemi et al. Ann med 2009), as well as the use of NMR (Mäkinen et al. Mol Syst Biol 2008).

The cell and molecular biology teamconcentrates on the effects of LPS as well as the AGEs and related defense mechanisms on the development of diabetic nephropathy. Key papers have been published on the MIF receptor in diabetic injury (Sanchez-Nino et al. JASN 2009) as well the OSBP related protein 3 (Lehto et al. J Cell Sci 2008).